Translation regulation in Trypanosoma brucei

布氏锥虫的翻译调控

基本信息

批准号：
7741107
负责人：
Salvador Z. Tarun
金额：
$ 16.06万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-15 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7741107
关键词：
Affect Affinity Chromatography African Trypanosomiasis Animal Diseases Binding Biochemical Biological Biological Assay Biology Cell Cycle Cell division Cell physiology Cessation of life Co-Immunoprecipitations Complex Data Development Differentiation and Growth Disease Drug Delivery Systems Drug Design Environment Epitopes Eukaryota Eukaryotic Initiation Factor-4E Gene Expression Gene Targeting Genes Genetic Transcription Genetic Translation Goals Grant Growth Homologous Gene Human Insecta Life Cycle Stages Malignant Neoplasms Mass Spectrum Analysis Messenger RNA Morphology Organelles Organism Parasites Pathogenesis Pathway interactions Pattern Peptide Initiation Factors Pharmaceutical Preparations Play Poly(A)-Binding Proteins Process Property Proteins RNA Binding RNA Caps RNA Interference RNA Processing Regulation Relative (related person)Repression Research Research Personnel Reverse Transcriptase Polymerase Chain Reaction Ribosomes Role Sedimentation process Staging Testing The Sun Translating Translation Initiation Translational Regulation Translations Trypanosoma Trypanosoma brucei brucei Two-Dimensional Gel Electrophoresis Vertebrates Work Yeasts antitumor drug cell type design drug discovery genome database in vivo insight mRNA Stability man novel pathogen promoter protein complex protein expression

项目摘要

DESCRIPTION (provided by applicant): Trypanosoma brucei is a group of pathogenic protozoans causing a spectrum of infectious human and related animal diseases that can be fatal and economically devastating. The long term goal of the application is to determine how translational control might regulate gene expression patterns in T. brucei that underlie its growth, differentiation and pathogenesis. It attempts to establish a rational framework in understanding how different genes, which are not controlled by transcription in this organisms, might coordinate their expression by translational means during the parasite's complex life cycle between its human and insect hosts. To examine this problem, the study will focus on elucidating the biological roles and translational functions of 4 different homologues of elF4E in this organism. They display unique structural features from those of their human hosts. In many organisms elF4Es play central role in the recruitment of mRNAs in translation and act as key growth and differentiation regulator by virtue of their rate limiting and coordinating function in translation initiation and thus, proven to be good target for anti-tumor drugs in humans. Their roles in Trypanosome biology is unclear, but elucidation of their function might yield promising avenues for drug design. To accomplish these aims the homologues would be systematically down-regulated by RNAi for their expression and examine the consequences of their loss in the growth, cell cycle and differentiation of the parasite. Their protein associations and mRNA targets will also be examined by affinity purification-Mass spectrometry, and mRNA co-immunoprecipitation, respectively, to determine their mechanistic functions and their downstream gene targets for regulation. Therefore these studies should provide crucial insights into how elF4E-dependent translation impacts the sun/ival of these important parasites. This study should be relevant in unveiling gene expression control pathways, perhaps unique to the parasite, that underlie cellular processes required in adapting to diverse and harsh host environments. The potential of 4E homologues to play central roles in this process can pave the way for possible avenues for drug targeting.

描述（由申请人提供）：布氏锥虫是一组致病性原生动物，可引起一系列传染性人类和相关动物疾病，这些疾病可能是致命的并具有经济破坏性。该应用的长期目标是确定翻译控制如何调节布氏锥虫的基因表达模式，从而促进其生长、分化和发病机制。它试图建立一个合理的框架来理解在这种生物体中不受转录控制的不同基因如何在寄生虫在人类和昆虫宿主之间的复杂生命周期中通过翻译手段协调它们的表达。为了研究这个问题，该研究将重点阐明 elF4E 的 4 个不同同源物在该生物体中的生物学作用和翻译功能。它们表现出与人类宿主不同的独特结构特征。在许多生物体中，elF4E 在翻译过程中招募 mRNA 中发挥着核心作用，并凭借其在翻译起始中的限速和协调功能而充当关键的生长和分化调节因子，因此被证明是人类抗肿瘤药物的良好靶标。它们在锥虫生物学中的作用尚不清楚，但阐明它们的功能可能会为药物设计带来有希望的途径。为了实现这些目标，将通过 RNAi 系统地下调同源物的表达，并检查它们的丢失对寄生虫的生长、细胞周期和分化的影响。它们的蛋白质关联和 mRNA 靶标也将分别通过亲和纯化质谱和 mRNA 免疫共沉淀进行检查，以确定它们的机制功能和下游基因靶标进行调节。因此，这些研究应该为 eF4E 依赖性翻译如何影响这些重要寄生虫的 sun/ival 提供重要的见解。这项研究应该与揭示基因表达控制途径相关，这可能是寄生虫所独有的，是适应多样化和恶劣宿主环境所需的细胞过程的基础。 4E 同系物在这一过程中发挥核心作用的潜力可以为药物靶向的可能途径铺平道路。